Prenatal Alcohol Exposure and Neurobehavioral Development Where Is the Threshold ?

M of the research on pre­ using a variety of assessment instruments from a Seattle cohort of children studied natal alcohol exposure has on children at various ages from infancy by Streissguth and colleagues (1983). focused on the hypothesis to late childhood. These children were born to approxi­ that drinking during preg­ One important issue is the level of mately 5001 predominantly white, middle­ nancy causes structural and biochemical maternal drinking necessary before neuro­ class women in the mid­1970’s. In alterations in the developing brain of the behavioral impairment is seen. Because the contrast, a recent study conducted in fetus. These alterations are thought to body has the ability to tolerate low doses Detroit (Jacobson et al. 1993) examined of most toxic substances, adverse effects affect many aspects of intellectual and 480 economically disadvantaged, black are seen only when exposure exceeds a behavioral function, including attention, infants. In both studies, mothers were certain minimum threshold dose. Severe activity level, and information­processing recruited during pregnancy. All moderate effects of alcohol, such as fetal death, speed. Deficits in these aspects of neuro­ to heavy drinkers and randomly selected mental retardation, and the craniofacial behavioral functions can be measured by lower level drinkers and abstainers were deformities associated with fetal alcohol syndrome (FAS), have relatively high invited to participate (see table 1 for JOSEPH L. JACOBSON, PH.D., is professor thresholds, occurring only in the most drinking levels). of psychology in the psychology depart­ heavily alcohol­exposed fetuses. Sokol The data from these two longitudinal2 ment, Wayne State University, Detroit, and colleagues (1988) estimate that the cohort studies form the basis of this arti­ Michigan. threshold for FAS is consumption by the cle. We describe three types of dose­ mother of approximately 42 standard drinks response relationships reported for SANDRA W. JACOBSON, PH.D., is research (21 ounces of absolute alcohol) per week drinking during pregnancy, introduce professor of psychology in the psychology around the time of conception (table 1). alternative approaches for determining department, Wayne State University, Even at this level, however, not all children threshold values, review data on the Detroit, Michigan. will exhibit FAS (Sokol et al. 1986). thresholds found for neurobehavioral Only a few studies that have focused on The Detroit Prenatal Alcohol Exposure the effects of alcohol on neurobehavioral 1The number of women fluctuated at different phases and Infant Cognition Study was support­ development have investigated thresholds of the study. ed by National Institute on Alcohol Abuse (Jacobson et al. 1993; Streissguth et al. and Alcoholism grants R01–AA06966 1983). Most of the initial data on thresh­ 2Longitudinal studies examine the same group of and P50–AA0706. olds for neurobehavioral effects came people at intervals over time as they age.

M uch of the research on pre using a variety of assessment instruments from a Seattle cohort of children studied natal alcohol exposure has on children at various ages from infancy by Streissguth and colleagues (1983). focused on the hypothesis to late childhood. These children were born to approxi that drinking during preg One important issue is the level of mately 500 1 predominantly white, middle nancy causes structural and biochemical maternal drinking necessary before neuro class women in the mid1970's. In alterations in the developing brain of the behavioral impairment is seen. Because the contrast, a recent study conducted in fetus. These alterations are thought to body has the ability to tolerate low doses Detroit (Jacobson et al. 1993) examined of most toxic substances, adverse effects affect many aspects of intellectual and 480 economically disadvantaged, black are seen only when exposure exceeds a behavioral function, including attention, infants. In both studies, mothers were certain minimum threshold dose. Severe activity level, and informationprocessing recruited during pregnancy. All moderate effects of alcohol, such as fetal death, speed. Deficits in these aspects of neuro to heavy drinkers and randomly selected mental retardation, and the craniofacial behavioral functions can be measured by lower level drinkers and abstainers were deformities associated with fetal alcohol syndrome (FAS), have relatively high invited to participate (see table 1 for JOSEPH L. JACOBSON, PH.D., is professor thresholds, occurring only in the most drinking levels). of psychology in the psychology depart heavily alcoholexposed fetuses. Sokol The data from these two longitudinal 2 ment, Wayne State University, Detroit, and colleagues (1988) estimate that the cohort studies form the basis of this arti Michigan.
threshold for FAS is consumption by the cle. We describe three types of dose mother of approximately 42 standard drinks response relationships reported for SANDRA W. JACOBSON, PH.D., is research (21 ounces of absolute alcohol) per week drinking during pregnancy, introduce professor of psychology in the psychology around the time of conception (table 1).
alternative approaches for determining department, Wayne State University, Even at this level, however, not all children threshold values, review data on the Detroit, Michigan.
will exhibit FAS (Sokol et al. 1986

DOSERESPONSE PATTERNS
For some behaviors, such as mental de velopment, even the smallest dose of alcohol prenatally appears to have some adverse effect on the fetus, and the severi ty of the effect increases gradually with increasing levels of exposure (see figure  1A). This doseresponse relationship can be described as "linear with no apparent threshold." However, most neurobehav ioral outcomes are not so sensitive. Rath er, they seem to have relatively high thresholds, above which the effect then becomes more severe with increased exposure (figures 1B and 1C).
In some studies, step functions have been reported. As in figures 1B and 1C, little effect is seen below an observed threshold, but, unlike figures 1B and 1C, the effect does not appear to become more severe with increased exposure above the threshold. The effect occurs in one "step" at the threshold level of alcohol consump tion and remains steady, regardless of how high consumption rises above that level. Although the stepfunction pattern is fairly common in alcohol studies, it does not make complete sense toxicologi cally, because severity of effect should increase with additional exposure. In some cases, the appearance of a step function may be a result of not including enough heavily exposed children in the sample, which can lead to an under estimate of the severity of the effect at the highest doses.

DETERMINATION OF D OSERESPONSE AND THRESHOLD
Thresholds can be determined more pre cisely with laboratory animals than with humans. In animal studies, the amount of prenatal alcohol exposure can be carefully monitored and controlled, and potentially confounding factors, such as poor diet and exposure to other harmful substances (e.g., smoking), can be prevented. In humans, information on prenatal alcohol consumption is obtained by selfreports, and confounding factors cannot be elimi nated. In other words, if a neurobehav ioral deficit is found in a child, statistical analyses must be used to determine whether prenatal alcohol consumption is responsible for the deficit instead of smoking, poor eating habits, or poor parenting post partum.

Animals
Animal studies are used to determine a median lethal dose (LD50) of a toxic substance-the dose at which half of the fetuses exposed will die. It is assumed that individual differences in sensitivity to the exposure are distributed around the LD50; some fetuses will die at a lower dose and others will survive an even high er dose (Klaassen 1986). If a large num ber of different doses are tested, with a large number of animals per dose, an S shaped curve is observed (represented by the fetal death curve in figure 2). The threshold is the dose of alcohol at which all but the most vulnerable fetuses are affected. Certain outcomes are expected to have lower thresholds than others. Death would be expected to take place at the highest threshold, whereas milder forms of damage would occur at lower doses (see figure 2).

Humans
Data Collection. Two longitudinal studies have found that levels of pregnancy drink ing reported by women who were inter viewed after giving birth were markedly higher than those reported by women who were interviewed during pregnancy (Ernhart et al. 1989;Jacobson et al. 1991). Ernhart and colleagues (1989) found that one developmental outcome-physical anomalies, such as facial and limb de fects-was predicted better by reports of pregnancy drinking taken 5 years after giving birth than by drinking reports ob tained during pregnancy. The data from Jacobson and colleagues' Detroit study, on the other hand, suggest that drinking reports obtained during pregnancy are more accurate. Retrospective reports obtained at 13 months post partum were only weakly related to birth size and did not relate to any of the neurobehavioral outcomes shown in table 2, all of which were associated with reports of drinking during pregnancy (e.g., Jacobson et al. 1993). The thresholds reviewed here are based on maternal drinking reported during pregnancy.

Data Analysis.
In the Detroit study, we used the statistical technique of multiple regression analysis to test whether prena tal alcohol exposure adversely affects the neurobehavioral outcomes assessed. This technique is used to rule out other poten tially harmful factors, such as smoking, that may occur along with pregnancy drinking. A broad range of such potential confounding influences, including amount of prenatal care, smoking and illicit drug use during pregnancy, and quality of parenting, were measured and, where necessary, controlled for with the regres sion analysis (see Jacobson et al. 1993). A neurobehavioral deficit was attributed to prenatal alcohol exposure only when the odds were less than 1 in 20 (p < 0.05) that the deficit was due to chance after adjust ment for the effects of the potential con founders. If a neurobehavioral outcome was found to be influenced significantly by alcohol exposure, it was subsequently evaluated for a threshold to assess the level of alcohol exposure at which a response was seen.
To evaluate doseresponse patterns, we separated levels of alcohol exposure into discrete groups and plotted group means for each neurobehavioral outcome at each exposure group (adjusted statisti cally for potential confounding influ ences) (figure 1). To create exposure groups, we started with the consumption levels used in the 1988 National Health Interview Survey: abstainer, light, moder ate, and heavy (for actual quantities of alcohol consumed at these levels, see table 1). Given the large number of sub jects available in the light group, we sub divided that group by creating a "very light" group. Also, for some developmen tal outcomes, data were available for a suf ficiently large number of heavily exposed infants to create a "very heavy" group. Because virtually all of the moderate and heavydrinking women concentrated their drinking on a few days each week, the values used for plotting are presented in terms of ounces of absolute alcohol per week.
In the Seattle study, mothers were interviewed during the fifth month of gestation about their drinking during the "month or so prior to pregnancy recogni tion" and during pregnancy. The associa tion between neurobehavioral deficits and early pregnancy drinking was generally stronger than the association between neurobehavioral deficits and midpregnan cy drinking (e.g., Streissguth et al. 1984), leading the researchers to suggest that the human infant might be particularly sensi tive to alcohol exposure during early pregnancy. However, in the study of Detroit infants exposed to alcohol at similar levels, neurobehavioral effects were associated more strongly with later pregnancy drinking than with drinking around the time of conception.
The Detroit study used a more detailed selfreport procedure, in which mothers were interviewed at each prenatal clinic visit regarding their drinking on a day byday basis during the preceding 2 weeks. The interviewer started out by asking the following questions: I would like you to think back to last Friday. What did you do? Did you go out? Did you relax in front of the TV? Did you have a drink? What were you drinking that evening? How do you drink that bever age? By the can? By the glass? How big a glass do you usually drink?
Cognition, fine motor coordination, and language skills are affected even at the lowest prenatal alcohol exposure, indicating no threshold for these neurobehavioral outcomes.

Level of Maternal Drinking During Pregnancy
Abstainer Very Light Light Moderate Heavy Very Heavy The average length of each visual glance made by the infant while inspecting a visual stimulus (see Jacobson et al. in press) has a threshold that appears to be at the heavy drinking level and the length of the glance increases with increasing exposure to alcohol.  The stronger relationships between pregnancy drinking and neurobehavioral deficits in the Detroit study suggest that the detailed interview procedure may provide a more reliable assessment of pregnancy drinking than the onetime midpregnancy report used in Seattle.

REVIEW OF FINDINGS
The neurobehavioral outcomes tested for thresholds in the Seattle study are summa rized in table 3. Although some measures were found to have no threshold, notably for reaction times at 4 and 7 years of age, most measures appear to have thresholds ranging from 7 to 28 standard drinks per week, as measured prior to pregnancy recognition or at midpregnancy. The thresholds detected for neurobehavioral outcomes in the Detroit study (table 2) are in the same range, although the values on certain measures, such as mental and motor development, differ between the two studies. The data from both studies suggest that most adverse neurobehavioral effects are not seen below seven standard drinks per week. In fact, studies that have included mostly mothers who drink fewer than seven standard drinks per week dur ing pregnancy generally have failed to detect effects on neurobehavioral develop ment in infancy (e.g., Greene et al. 1991), supporting the suggestion that seven standard drinks per week is a threshold level for most neurobehavioral effects (Jacobson et al. 1993).
Although the neurobehavioral out comes shown in tables 2 and 3 were tested statistically to ensure that the alcohol effect is not attributable to other con founding factors, the specific threshold values listed in these tables were not all tested for significance. In many cases, the number of children exposed to alcohol above the threshold was too small to test for statistical significance. The conclusion that the threshold for neurobehavioral effects lies in the range of 7 to 28 standard drinks per week is based on the consisten cy of the data across a large number of neurobehavioral outcomes rather than on the statistical significance of the individual threshold values observed.
It should be noted that because few pregnant women drink every day, seven standard drinks per week typically repre sents relatively heavy doses of alcohol on drinking days. For example, the mothers in the Detroit sample who drank more than 7 standard drinks per week exposed their Ideal dose-response curves for four domains affected by toxic exposure during fetal development. As dose of a toxic substance increases, more fetuses are at risk of injury and effects become more severe, ranging from functional teratogenesis, which includes neurobehavioral outcomes, to fetal death.
1 The LD50 represents the median lethal dose of a toxic substance at which half of the fetuses exposed will die. SOURCE: Vorhees 1986. infants to an average of 6 drinks per day (at a range of 1.2 to 24.8 drinks) on an average of 2.6 days per week (at a range of 0.6 to 7.0 days) (Jacobson et al. 1993).
Alcohol's adverse effects on the chil dren's neurobehavior were by no means limited to the children of alcohol abusers. The majority of the Detroit mothers who drank more than seven standard drinks per week were negative on the Michigan Alcoholism Screening Test (MAST), indicating that their drinking was not marked by the psychosocial sequelae of alcohol abuse. Even those moderate and heavydrinking mothers whose infants performed poorly on the tests shown in table 2 (i.e., in the bottom 10th percentile of the distribution) were no more likely to be positive for alcoholism on the MAST than those mothers whose infants per formed adequately or well.

NEUROBEHAVIORAL OUTCOME MEASURES
According to Vorhees (1986) and others, neurobehavioral outcomes appear to be the most sensitive index of the fetal toxic ity, or teratogenicity, of a toxic substance that affects multiple developmental do mains (e.g., fetal death, congenital mal formations, growth retardation, and neurobehavioral function) (figure 2). Levin and colleagues (1992) have pointed out, however, that structural changes in the brain can now often be detected at even lower levels of exposure than are neurobehavioral deficits. For example, in animal studies of halothane (a surgical anesthetic) exposure during development, structural abnormalities in the connec tions between the nerve cells of the hip pocampus were evident at much lower levels of exposure than the shortterm memory deficits traditionally associated with damage to that brain area. Such findings indicate that extremely low levels of teratogens, such as halothane and alcohol, may cause structural damage not severe enough to cause obvious ef fects on function. Improvements in the ability to measure neurostructural changes more precisely make it likely that such changes will be seen at increasingly lower doses. Ultimately, however, the informa tion of greatest interest is the lowest dose at which effects are seen that have a mean ingful impact on neurobehavioral or other function.
Within the broad domain of neuro behavior, specific areas of function (e.g., motor coordination, activity level, sus tained attention) are likely to vary in their sensitivity to different toxic agents. For example, in the Detroit study, the thresh old for the 13month Bayley Psychomotor Development Index, which assesses gross motor development, was much higher than the threshold for the Bayley Mental Development Index, which assesses cognition, fine motor coordination, and language skills (table 2).
Thresholds vary not only by functional domain but also within domains, depend ing on the sensitivity of the measures used. For example, two measures of cognitiveprocessing speed were used in the Detroit study. The first, mean duration of visual fixation, measures the average length of time that an infant looks at each of two pictures or objects placed side by side. Infant development researchers have found that in infancy, shorter looks are associated with more rapid encoding of visual information (Colombo et al. 1991) and predict higher childhood IQ scores (Sigman et al. 1991). Thus, shorter looks apparently indicate the ability to assimilate and process information more quickly.
The second measure of infant cognitive processing speed used in the Detroit study was reaction time in shifting gaze back and forth in response to an image flashing in alternating leftright positions on a video screen (Haith et al. 1988). Reaction time also appears to reflect speed of in formation processing and, in fact, infants with slower times on the fixationduration measure also respond more slowly to the onset of the visual stimulus in the reaction time measure (Jacobson et al. 1992a).
Prenatal alcohol exposure was associ ated with slower processing speed on both speed of processing measures (Jacob son et al. in press;Jacobson et al. 1992b); however, the reactiontime measure proved markedly more sensitive, detect ing effects at 7 drinks per week (figure 1C), compared with a 14drinks per week threshold for fixation duration ( figure  1B). Similarly, the threshold for effects on IQ at 7 years (Streissguth et al. 1989) was lower than at 4 years , presumably due to the superior reliability of the test at the older age (table 3). These data show the extent to which neurobehavioral threshold values depend on the sensitivity and reliability of the testing instruments.

FUNCTIONAL SIGNIFICANCE
As noted earlier, some neurobehavioral measures appear to have no threshold; they are so sensitive that effects are seen even at extremely low levels of alcohol exposure. For example, the data in figure  1A suggest that the mental development of infants whose mothers drank at light levels (an average of 0.85 standard drinks per week during pregnancy) is poorer  Jacobson et al. 1992b. *Jacobson et al. in press. this outcome is examined in terms of the proportion of infants who exhibit poor   Jacobson et al. 1993 than that of the infants of abstainers. However, because reductions in neuro behavioral scores may be only a few points or fractions of a second at low doses, particular consideration should be given to the functional significance of alcohol's neurobehavioral effect. That is, to what extent does the deficit have a meaningful impact on the child's ability to acquire information or to perform an intellectual or motor task? Criteria for functional significance exist for some standardized measures, such as IQ, but not for experimental measures, such as the fixationduration and reactiontime measures described above. Even on standardized tests, estab lished criteria identify mental retardation or "borderline" retardation but cannot be used to evaluate the functional signifi cance of lower scores within the normal range. In the absence of established crite ria, we use the bottom 10th percentile of the distribution or one standard deviation below the mean as provisional criteria for determining the degree to which exposure to alcohol is associated with an increased incidence in what might be considered poor performance on a test. Table 4 shows the incidence of poor mental development performance (i.e., number of low scores) at each level of prenatal alcohol exposure. In contrast with the analysis that compares group means (figure 1A), which suggested subtle effects at even the lowest levels of exposure, the analysis based on the poor performance criterion indicates no in creased incidence in functional impair ment below seven standard drinks per week. Below this threshold, the rate of poor performance was in the range of what might be expected by chance.
Researchers are generally reluctant to set criteria for functional significance. To evaluate properly the functional signifi cance of scores on infant tests, detailed prospective longitudinal data are needed to determine what level of infant perfor mance is associated with poor perfor mance later in childhood. Even if such data were available, the limited predictive power of most infant measures would raise questions about the usefulness of the criteria selected. In childhood, the degree to which performance on a test is indica tive of functional limitations outside the testing situation remains a matter of clinical judgment, which quantitatively oriented researchers are usually hesitant to make.

IMPLICATIONS FOR DEFINING THRESHOLD
In human neurobehavioral studies, thresh old is usually defined in terms of the level of exposure to a toxin below which aver age group performance is not adversely affected. As illustrated by data from lab oratory experiments with animals, howev er, there are typically marked individual differences in vulnerability to any given exposure (figure 2). Because the threshold values derived from human studies are based on group averages, it is not appro priate to infer that exposure just below a threshold level is necessarily "safe," be cause some individuals could be markedly more sensitive than others.
In evaluating risk associated with exposure to environmental and food contaminants, a margin of safety is usual ly incorporated to allow for individual differences in sensitivity. Where human data are available, a margin of safety of a factor of 10 is used for this purpose (Sette and Levine 1986). Taking this approach, it is possible to divide the threshold value of 3.5 ounces of absolute alcohol per week by 10 and conclude that 0.35 ounces per week (one drink every 10 days) dur ing pregnancy is likely to be "safe." On the other hand, even if no functional deficits are associated with a given level of exposure in infancy and childhood, there is the potential for unobservable neurostructural damage, which could lead to functional deficits when the child is stressed or challenged by a complex task (Riley 1990), or when the child reaches old age.
Because alcohol exposure has no apparent benefit for the developing fetus and is not necessary for the health and wellbeing of the mother, some clinicians and health officials have argued that the best policy is to advise pregnant women not to drink at all during pregnancy.
Given the relatively high levels of alco hol at which any functionally significant deficits have been documented, however, other clinicians find it difficult to justify the need for complete abstinence. The Surgeon General, however, has advised that all pregnant women abstain from drinking throughout pregnancy, because there is no way to determine definitively which babies may be at risk for damage from very low levels of alcohol exposure. ■

ALCOHOL AND MINORITIES
The current issue of NIAAA's Alcohol Alert series examines drinking patterns among minority groups in the United States.